Quasi-Emulsion Precipitation of Pharmaceuticals. 1. Conditions for Formation and Crystal Nucleation and Growth Behavior

Induction time and crystal morphology changed with agitation during the precipitation of salicylic acid in viscous, aqueous low molecular weight poly(ethylene glycol) 300 (PEG300) solutions with water as the antisolvent. Further, if antisolvent precipitations of either salicylic acid or methylparaben in aqueous PEG300 were conducted by equal volume mixing in a confined impinging jet, the exiting solution was optically clear and exhibited induction times as long as days. Significant mechanical agitation or seeding of the solutions induced rapid crystallization. Light scattering and particle size analysis supported the idea that a quasi-emulsion was formed consisting of well-dispersed, solute-stabilized droplets (diameters of 100−1000 nm) of the viscous solution in the less viscous antisolvent. In agreement with Taylor's droplet breakup theory, when a viscous fluid is added to a less viscous one, a quasi-emulsion can form if the viscosity ratio is above ∼3 and if a precipitatable solute is present. Induction time in these systems was a function of supersaturation ratio and mixing conditions. Generally, nucleation and growth occur on the outside of the droplets, but growth can occur within the droplets producing spherical crystals. Applications of quasi-emulsion precipitation (QEP) include polymorph control and chiral isomer separations from racemic conglomerates.